This invention relates generally to drug delivery devices and methods of use relating to same, and more particularly relates to a catheter for delivery of an agent formulation requiring modification of the agent formulation prior to delivery.
Precise and accurate delivery of drugs or therapeutic agents to a specific treatment site within a subject represents a substantial challenge in the design of drug delivery systems. Site-specific drug delivery can be particularly challenging when the drug is to be delivered to the subject long-term, e.g., over several hours to several days, weeks or months.
One approach to long-term site-specific drug delivery involves the use of implantable delivery systems, e.g., electrochemical, electromechanical, biodegradable or osmotically-driven drug delivery devices. While these implantable systems avoid the need for repeated injections often associated with long-term drug therapy administration, they have a number of limitations. First, the treatment sites which they can access are limited. In addition, sites to which drug delivery is required can be fragile, sensitive or inaccessible and thus often not amenable to insertion of an implant. The size of the delivery device can also be problematic, since the size of a reservoir large enough to contain an amount of drug sufficient to provide weeks to months of delivery can be quite large and impracticable. Smaller reservoirs can be used and the reservoir refilled with drug during the course of the treatment; however, manipulating, re-filling and/or re-positioning an implantable device can have serious consequences, e.g., increased risk of infection, patient discomfort, and increased costs.
An alternative approach is to provide formulations having high concentrations of drug, such that delivery of small amounts of formulation are sufficient to provide for a desired therapeutic effect. The total amount of formulation required for long-term therapy is thus substantially decreased, thus minimizing the size requirements for the reservoir of the device used to accomplish delivery. While this approach has met with some success, there are still serious limitations for certain therapeutics and for chronic delivery. For example, formulations with high concentrations of drug can be toxic to cells at the delivery site, or can result in irritation, inflammation, and tissue damage at the delivery site. Many drugs are insoluble or unstable at physiological pH (e.g., around pH 4-pH 8), and can only be stored long term in formulations of non-physiological pH (e.g., pH less than about pH 4, or pH greater than about pH 8). Delivery of such non-physiological pH formulations can cause adverse side effects, particularly at the delivery site. In addition, many drugs are stable as inactive prodrugs, but are relatively unstable once modified to the active species. However, providing a drug delivery device with a means for converting the prodrug to an active drug can add to the size and bulkiness of the device. Furthermore, where the delivery site is far from the drug delivery device, the stability of the active drug may be compromised during the course of its transit to the delivery site.
There is thus a need in the field for devices that allow the use of a smaller drug reservoir and highly concentrated, stable drug formulations, provide for safe delivery of same to a treatment site for long-term therapy, and provide for an efficient means for modification of the drug (e.g., from a prodrug to an active drug, modification of the formulation to a physiologically relevant pH, to an active and physiologically relevant state prior to release into a body structure, and the like).
The present invention provides a catheter for use in delivering formulation that allows modification of the formulation prior to or concomitant with its transport or at a delivery site. The catheter comprises an elongate body, which defines an inner lumen extending between the proximal and distal ends, and a modifying element, which provides for modification of one or more components of a formulation prior to or concomitant with release at the delivery site.
In one embodiment, the modifying element modifies the formulation by allowing for passage of water from the environment of use through a wall of the modifying element and into the inner lumen, thereby diluting the formulation. In a related embodiment, a modifying agent is associated with the wall of the modifying element such that influx of water through the wall displaces the modifying agent, carrying it into the inner lumen where it mixes with the formulation.
In another embodiment, the modifying element has immobilized modifying agent (e.g., immobilized on an inner wall of the modifying element) such that passage of formulation through the inner lumen results in modification of the formulation or a formulation component(s).
In one aspect, the catheter is provided in connection with a drug delivery device to comprise a drug delivery system whereby the drug delivery device and the catheter are operatively connected to provide for delivery of drug from a reservoir in the drug delivery device, through the catheter, and to the delivery site. The drug delivery device may be completely or partially implanted, or may be retained at a site external to the body with at least a portion of the catheter implanted to direct the agent to the desired delivery site within the body. An exemplary drug delivery device for use in the system is configured to have at least one compartment for storing the formulation, e.g., a reservoir.
In another aspect, the present invention provides a method for delivery of a drug or therapeutic agent to a treatment site in a subject by implanting at least the distal end of a catheter of the invention at a desired delivery site and introducing a drug or agent to the delivery site through the catheter. The catheter can be used to dilute an agent in the formulation and/or increase the surface area of release prior to delivery to a delivery site, thus reducing side effects that may be caused from the delivery of a concentrated drug to a site.
In another aspect, the invention features a method for modifying an agent formulation prior to delivery to a subject by implanting at least a distal portion of a catheter according to the invention at a delivery site in a subject, and introducing a formulation comprising an agent into the inlet of the elongate body. The introduced formulation flows through the elongate body passageway and past an inner wall of the modifying element so as to effect modification of the formulation or the agent (or other component) in the formulation is modified prior to release at the delivery site in the subject. The formulation or formulation component can be modified by, for example, dilution during transit through the catheter. increasing or decreasing pH prior to exit at the delivery site, or, where the agent is a prodrug, the prodrug is converted to an active drug prior to exit at the delivery site.
A primary objective of the invention is to provide a catheter that can facilitate delivery of formulations comprising high concentrations of a drug or other agent with minimal detriment to the surrounding tissue.
It is another object of the invention to provide for modification of a formulation component prior to delivery to a delivery site, e.g., conversion of a prodrug to an active drug, adjustment of pH, or for dilution of a formulation immediately prior to delivery to the delivery area.
Another object of the invention is to provide a drug delivery system that can be readily handled, implanted and adapted for use in accurate, consistent and reliable delivery of drug at a particularly low volume rate, e.g., microliter or submicroliter quantities of a formulation per day.
It is yet another object of the invention to provide a drug delivery system compatible for use with a highly concentrated drug formulation so that a smaller drug reservoir volume of the drug delivery device is required, thereby reducing the volume of formulation and the size of the drug reservoir that must be in the drug delivery device, while allowing dilute or physiologically active and non-toxic drug formulation to be delivered at the site of desired action. This permits reduction in size of the entire drug delivery device, thus increasing comfort and mobility for the patient.
It is another object of the invention to provide a catheter that is suitable for delivery of drug to a distal delivery site within a subject, particularly sites that are highly sensitive or fragile, e.g., the spinal cord. It is yet another object of the invention to provide a mechanism by which inactive drug can be stored in a drug reservoir and converted to an active state prior to delivery to the delivery area.
Another object of the invention is to provide a catheter that can be used with a variety of drug delivery devices.
An advantage of the invention is that the catheter can facilitate delivery of extremely small volumes of drug, e.g., submicroliter volumes, and at low volume delivery rates, yet is easily handled, e.g. by a clinician during implantation.
Another advantage of the invention is that an inactive form of a drug can be stored in a drug reservoir and converted to an active state prior to delivery. This advantage allows stable, inactive formulations to be stored and converted to less stable, active states just prior to delivery.
These and other objects, advantages and features of the present invention will become apparent to those skilled in the art upon reading this disclosure in combination with the drawings, where like numerals refer to like components throughout.